The failure of the trophoblast to express MHC class II antigens is believed to be essential for survival of the fetus during pregnancy. It is therefore likely that strong evolutionary pressures to preserve reproduction would develop tight overlapping regulatory controls. We have identified two such control mechanisms which inhibit trophoblast class II expression. An upstream negative regulatory element (IAalphaNRE) in the promoter of the murine class II IAalpha gene that represses transcription specifically in trophoblasts. In addition, the class II transcription activator (CIITA), the master regulator of class II expression is not transcribed in trophoblast cells, nor can it be induced by IFN-gamma or other cytokines that upregulate class II in most other cell types. The goals of this grant are to further define the underlying mechanisms responsible for the inability of the trophoblast to express class II and the physiological relevance of this to fetal persistence. Hopefully, these studies will also elucidate fundamental control mechanisms for class II expression that have application to other areas of clinical relevance such as cancer and autoimmunity.